BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain

Autor: Sabine Bailly, Mariela Subileau, Marie Bidart, Sandrine Levet, Emmanuelle Tillet, Nicolas Ricard, Michel Samson, Christine Mallet, Jean-Jacques Feige, Laurent David
Přispěvatelé: Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Male
medicine.medical_treatment
Endothelial cells
Endogeny
Smad Proteins
ALK1
Serine
MESH: Hepatocytes
Mice
0302 clinical medicine
Growth Differentiation Factor 2
MESH: Animals
MESH: Serine Endopeptidases
Furin
Aorta
0303 health sciences
MESH: Middle Aged
Kinase
Serine Endopeptidases
MESH: Aorta
Middle Aged
Ligand (biochemistry)
3. Good health
Cell biology
Growth Differentiation Factors
Cytokine
Blood
Biochemistry
Liver
MESH: Epithelial Cells
030220 oncology & carcinogenesis
MESH: Proprotein Convertases
Molecular Medicine
Phosphorylation
Female
Proprotein Convertases
Adult
MESH: Rats
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
BMP9
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Animals
Humans
Rats
Wistar
MESH: Growth Differentiation Factor 2
Molecular Biology
MESH: Mice
030304 developmental biology
Pharmacology
MESH: Humans
Epithelial Cells
MESH: Adult
MESH: Smad Proteins
Cell Biology
MESH: Rats
Wistar
MESH: Growth Differentiation Factors
MESH: Male
Rats
Bile Ducts
Intrahepatic
MESH: Bile Ducts
Intrahepatic
biology.protein
NIH 3T3 Cells
Hepatocytes
MESH: Female
Function (biology)
MESH: NIH 3T3 Cells
Zdroj: Cellular and Molecular Life Sciences
Cellular and Molecular Life Sciences, 2012, 69 (2), pp.313-24. ⟨10.1007/s00018-011-0751-1⟩
Cellular and Molecular Life Sciences, Springer Verlag, 2012, 69 (2), pp.313-24. ⟨10.1007/s00018-011-0751-1⟩
ISSN: 1420-682X
1420-9071
DOI: 10.1007/s00018-011-0751-1⟩
Popis: International audience; Bone Morphogenetic Protein 9 (BMP9) has been recently found to be the physiological ligand for the activin receptor-like kinase 1 (ALK1), and to be a major circulating vascular quiescence factor. Moreover, a soluble chimeric ALK1 protein (ALK1-Fc) has recently been developed and showed powerful anti-tumor growth and anti-angiogenic effects. However, not much is known concerning BMP9. This prompted us to investigate the human endogenous sources of this cytokine and to further characterize its circulating form(s) and its function. Analysis of BMP9 expression reveals that BMP9 is produced by hepatocytes and intrahepatic biliary epithelial cells. Gel filtration analysis combined with ELISA and biological assays demonstrate that BMP9 circulates in plasma (1) as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and (2) as a mature and fully active form (composed of the mature form associated with its prodomain). Analysis of BMP9 circulating levels during mouse development demonstrates that BMP9 peaks during the first 3 weeks after birth and then decreases to 2 ng/mL in adulthood. We also show that circulating BMP9 physiologically induces a constitutive Smad1/5/8 phosphorylation in endothelial cells. Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active (60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state.
Databáze: OpenAIRE
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